Triterpenoids, biosynthesized in plants by the cyclization of squalene, are used for medicinal purposes in many Asian countries; and some, like ursolic and oleanolic acids, are known to exhibit anti-inflammatory and anti-carcinogenic activity (Huang, et al. (1994) Cancer Res. 54:701-708; Nishino, et al. (1988) Cancer Res. 48:5210-5215). However, the biological activity of these naturally-occurring molecules is relatively weak, and therefore the synthesis of new analogs to enhance their potency has been undertaken (Honda, et al. (1997) Bioorg. Med. Chem. Lett. 7:1623-1628; Honda, et al. (1998) Bioorg. Med. Chem. Lett. 8(19):2711-2714). An ongoing effort for the improvement of anti-inflammatory and antiproliferative activity of oleanolic and ursolic acid analogs led to the discovery of 2-cyano-3,12-dioxooleane-1,9(11)-dien-28-oic acid (CDDO) and related compounds (Honda, et al. (1997) supra; Honda, et al. (1998) supra; Honda, et al. (1999) Bioorg. Med. Chem. Lett. 9(24):3429-3434; Honda, et al. (2000) J. Med. Chem. 43:4233-4246; Honda, et al. (2000) J. Med. Chem., 43:1866-1877; Honda, et al. (2002) Bioorg. Med. Chem. Lett. 12:1027-1030; Suh, et al. (1998) Cancer Res. 58:717-723; Suh, et al. (1999) Cancer Res., 59(2):336-341; Suh, et al. (2003) Cancer Res. 63:1371-1376; Place, et al. (2003) Clin. Cancer Res. 9:2798-2806; Liby, et al. (2005) Cancer Res. 65:4789-4798). Several potent derivatives of oleanolic acid were identified, including methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO-Me).
CDDO-Me suppresses the induction of several important inflammatory mediators, such as iNOS, COX-2, TNFα, and IFNγ, in activated macrophages. CDDO-Me has also been reported to activate the Keap1/Nrf2/ARE signaling pathway resulting in the production of several anti-inflammatory and antioxidant proteins, such as heme oxygenase-1 (HO-1). These properties have made CDDO-Me a candidate for the treatment of neoplastic and proliferative diseases, such as cancer. Moreover, synthetic triterpenoids have been found to induce apoptosis and differentiation and inhibit proliferation in human leukemia cells (Ikeda, et al. (2003) Cancer Res. 63:5551-5558; Konopleva, et al. (2002) Blood 99(1):326-335; Suh, et al. (1999) supra; Ito, et al. (2000) Mech. Dev. 97:35-45), induce osteoblastic differentiation in osteosarcoma cells (Ito, et al. (2001) Antimicrob. Agents Chemother. 45:1323-1336), enhance neuronal growth factor-induced neuronal differentiation of rat PC12 pheochromocytoma cells, and induce adipogenic differentiation of fibroblasts into adipocytes (Suh, et al. (1999) supra). CDDO-Me has also been found an effective drug for improving kidney function in patients suffering for renal/kidney disease using CDDO-Me (U.S. Pat. No. 8,129,429).